tbuckley/cabot-search huggingface dataset:
Artificial intelligence–powered tumor-infiltrating lymphocytes analyzer to reveal distinct immune landscapes in breast cancer by molecular subtype and HER2 score.
Authors: Seunghwan Shin, Soo Youn Cho, Eun Yoon Cho, So-Woon Kim, Minsun Jung, Seung-Geun Song, Yoojoo Lim, Soo Ick Cho, Sukjun Kim, Gahee Park, Heon Song, Minuk Ma, Donggeun Yoo, Chan-Young Ock
Journal: Journal of Clinical Oncology (2023)

1049 Background: Tumor-infiltrating lymphocytes (TIL) reflect an ongoing anti-tumor immune response in the tumor microenvironment (TME) and have been studied as a predictive as well as prognostic biomarker in breast cancer (BC). The immune profile differs depending on BC molecular subtypes, with triple-negative BC (TNBC) and HER2-positive BC more frequently infiltrated by higher numbers of TIL than hormone receptor (HR)-positive tumors. In this study, we analyze TIL and immune phenotype by molecular subtype in BC and explore differences based on HER2 scores using an AI-powered TIL analyzer. Methods: A total of 1,973 cases of BC with molecular subtype, HER2 immunohistochemistry (IHC) or in situ hybridization (ISH) results, and TIL analysis from H&amp;E slides from TCGA (n=1021), Samsung Medical Center (SMC, n=663), and KyungHee Medical Center (KHMC, n=289) were included in the analysis. The density of TIL were spatially analyzed from H&amp;E WSI, and the immune phenotype (IP) was analyzed for each 1 mm2-sized patch. Tumor microenvironment (TME) was categorized into three types: inflamed (TIL distributed intratumorally), Immune-excluded (TIL excluded, out of cancer stroma), immune-desert (scant TIL in TME), and the score for each IP was calculated as the percentage of the total patches in WSI. Results: TNBC showed the highest TIL density in both cancer epithelium (214.5 ± 299.7/mm2) and stroma (1133.3 ± 1245.9/mm2), and a high percentage of inflamed IP (35.7%), IS (28.4 ± 28.1) than other subtypes (inflamed IP: 17.5%, IS 16.2±20.2, both p&lt;0.001). HER2-positive BCs showed higher sTIL density (904.0 ± 901.7/mm2) compared to HR- positive BC (616.7 ± 794.1/mm2) but were associated with a higher percentage of immune-excluded IP (71.2%) and IES (57.6 ± 24.6). HR-positive BC had a high percentage of immune-desert IP (30.4%). In both HR-positive and negative BCs, higher IES was observed as the HER2 score increased. HER2-positive BC significantly showed a higher proportion of cancer stroma in the cancer region from WSI (Stromal ratio, 0.682 ± 0.149 vs. 0.578 ± 0.176, p&lt;0.001). Conclusions: Different TIL densities and IP were seen in BC for each molecular subtype, pointing to a distinct immune landscape. HER2 score was associated with immune-excluded IP despite having higher TIL density, which should be considered for immunotherapy in BC.
Combined role of the neutrophil/lymphocyte ratio and Neo-Bioscore in neoadjuvant therapy in HER2-positive early breast cancer.
Authors: Laura Sánchez Escudero, Stephanie S Cobelas Cartagena, David Morales Pancorbo, Juan L. Bayo
Journal: Journal of Clinical Oncology (2023)

e12613 Background: High neutrophil/lymphocyte ratio (NLR) is considered a poor prognostic factor in triple negative breast cancer but its role in HER2-positive early breast cancer (eHBC) and its relationship with Neo-Bioscore (Nb) scale (NbS) in neoadjuvant therapy (NeoT) has not been established. They could be predictive factors of response to double antiher2 blocking with Pertuzumab (Pz) and Trastuzumab (Tz). Methods: The efficacy of Chemo-trastuzumab (ChTz) versus Chemo-trastuzumab-pertuzumab (ChTzPz) was assessed in patients with eHBC treated at our center. We performed a comparative analysis of the pathological complete response (pCR) according to pre-treatment NLR and clinical NbS (Grade + clinical stage + estrogen receptor (ER) previous to NeoT) Univariate and multivariate retrospective study were performed using xi-square and binary logistic regression (v21 SPSS software). Results: 150 patients (Pts) with stage IIA to IIIC HBC were treated from 2014 to 2022. Mean age 52 years. 83 Pts (55.3%) received Chem-Tz and 67 Pts (44.7%) Chem-Tz-Pz. In the overall sample, the pCR was higher in the Tz-Pz group, 60% Vs 40%; OR 3.05 (95% CI 1.5-5.9). In the NLR &gt;2 subgroup, pCR was higher in Pts treated with Pz-Tz, 66.7% vs 33.3%; OR 4.2 (95% CI 1.5 – 11.07) If we combine Pts with both NLR ≥2 and clinical Nb ≥2, the pCR was significantly higher in the Tz-Pz group, 68.4% vs 11.8%; OR 16.25 (95% CI 2.7-94.8). In the multivariate analysis, Nb≥2, NLR ≥2 and double blockade with Pz are related to an increase in pCR (OR 1.29, OR 1.076 and OR 2.90 respectively), with significance for Pz (p=0.001). Conclusions: In our review, the combined use of Pz-Tz proves to be a more effective treatment than simple Tz blockade in the treatment of poor prognosis breast cancer. High NLR, despite being a poor prognostic factor, seems to be a predictor factor of pCR in Pts treated with Pz-Tz. The increase in NLR and clinical NbS are factors to take into account to predict the efficacy of NeoT in eHBC Pts. [Table: see text]
A phase 1b/2 dose escalation and expansion study of OP-1250 in combination with ribociclib or alpelisib in patients with advanced and/or metastatic estrogen receptor–positive (ER+)/HER2-negative (HER2-) breast cancer.
Authors: Virginia F. Borges, Arlene Chan, Nancy U. Lin, Margaret Eleanor Tonda, Mark Shilkrut, Carlos A. Alemany
Journal: Journal of Clinical Oncology (2023)

TPS1127 Background: Therapies targeting the estrogen receptor (ER) are standard of care in the management of ER+/HER2- metastatic breast cancer (MBC) and when administered concurrently with cyclin-dependent kinase (CDK) inhibitors are the most effective first-line therapy. CDK 4/6 inhibitors plus endocrine therapy improve progression-free survival and, for some agents, overall survival for patients with MBC. However, most patients will acquire resistance, highlighting an unmet need for more effective endocrine options in ER+ disease. OP-1250 is a small molecule oral complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity. OP-1250 potently inactivates both wild-type and mutant forms of ER, the latter of which confers ligand independent activity as a mechanism of resistance to standard of care endocrine therapies. In preclinical studies, OP-1250 in combination with CDK4/6 inhibitors demonstrated synergistic activity in models of both wild-type ER and those with ESR1 (the gene that encodes ER) activating mutations, and in brain metastasis. OP-1250 is orally bioavailable with a favorable pharmacokinetic (PK) profile supportive of once-daily dosing, and a low probability of drug:drug interactions, making it an attractive agent for patients with ER+/HER2- MBC. Methods: The study (NCT05508906) is an open-label, multicenter, 2-part study of OP-1250 in combination with either the CDK4/6 inhibitor ribociclib or the PI3K inhibitor alpelisib for patients with MBC. Eligibility includes adults with evaluable (measurable or non-measurable) ER+/HER2- recurrent, locally advanced or MBC confirmed by histology/cytology, ≤2 prior hormonal regimens (prior CDK4/6 inhibitors allowed) and ≤ 1 prior line of chemotherapy. Patients in the alpelisib arm must have a PIK3CA mutation. A total of 30 patients will be enrolled in each arm. The dose escalation cohorts will evaluate the safety and PK of varied OP-1250 doses (30mg, 60mg, or 120mg) administered orally (PO) every day (QD) in combination with approved dosages of either ribociclib 600 mg PO QD or alpelisib 300 mg PO QD to identify the recommended phase 2 doses (RP2D). The dose expansion cohorts will assess additional safety and PK parameters and further explore the anti-tumor activity of OP-1250 in combination with ribociclib or alpelisib. Tolerability, safety and PK of OP-1250 in combination with ribociclib or alpelisib constitute the primary endpoints. Overall response rate, clinical benefit rate and duration of response are key secondary endpoints. Enrollment at approximately 20 sites in the United States and Australia is ongoing. Clinical trial information: NCT05508906 .
Overall survival information and population correspondence for FDA cancer accelerated approval indications between 2006 and 2021.
Authors: Agnes Benedict, Gabor Szabó, Bridget Doherty, Silas Martin, Kinga Marczell
Journal: Journal of Clinical Oncology (2023)

e13653 Background: The US Food and Drug Administration (FDA) Accelerated Approval Program (AAP) was instituted to allow patients earlier access to medications that address large unmet need and are approved based on surrogate endpoints. Recently, approvals have been criticized for not providing overall survival data, and for confirmatory trials conducted in alternative populations. We investigated the availability of overall survival (OS) data for cancer accelerated approval (AA) indications and the correspondence between the population providing OS information and that of the original indication to assess the merit of these critiques. Methods: Approval letters and labels of cancer therapy products approved between January 1, 2006 and June 31, 2021 based on their verification status as of June 10, 2022 were identified from Drugs@FDA. Information was extracted irrespective of the final decision. Information about the exact indications and the trials that were used for AA and were cited for RA (confirmatory trial). OS data was searched for both AA and RA trials irrespective of approval dates, linked by NCT numbers identified in labels and letters. When OS was available only from the trial indicated for the RA, level of correspondence between the source of the OS data and the AA indication were described and then categorized in terms of the population characteristics, treatment lines, disease stage and changes in treatment regimen, to indicate level of correspondence. Results: OS data is available for 83% of closed AAs: 50 among the 57 converted and 12 among 18 withdrawn AAs. Further OS data was identified for seven AAs among the 55 ongoing reviews, creating a set of OS data for 69 out of the 130 total number of AAs identified. Exact or very good population overlap is evident in 50% of cases, defined as the availability of the trial reporting results for a population exact or very close to the original AA population; line change down was defined if the RA trial was conducted in an earlier line (without overlap with the original AA trial); and some additional categories were identified. Conclusions: Overall, OS information was available, and in half of the cases it was reported for a population very close to the original AA indication. Likely for ethical and practical reasons, RA trials are conducted in an indication that differs from the original AA indication and changes in the population was with the consent of the FDA. Policy discussions about AAP are incomplete without assessing its impact on survival and real-world considerations for conducting confirmatory trials. [Table: see text]
Demographic characteristics of encapsulated papillary carcinoma.
Authors: Andrew Luker, Xinxin Wu, Darby Keirns, Augustus Malan, Peter T. Silberstein, Beau Hsia
Journal: Journal of Clinical Oncology (2023)

e12562 Background: Encapsulated papillary carcinoma (EPC) is a very rare form of breast cancer characterized by fibrous encapsulation and expansile growth, causing 1-2% of all cases. A summary of 25 case reports found that although two-thirds of cases had invasive growth, EPC responded well to local therapy and is considered a favorable diagnosis as a result. Because classification and diagnostic criteria for EPC continues to be debated, examination of the demographics could prove useful in determining trends. Methods: A retrospective cohort study done using data from the National Cancer Database (NCDB) from 2004–2020 found 314 patients with an EPC diagnosis through histology. The following demographics were considered: age, sex, race, Hispanic identity, distance from residence to treatment facility, insurance coverage, type of facility, and Charleson-Deyo score. These variables were then analyzed through descriptive statistics. Results: 314 patients were identified with a steadily increasing number of cases diagnosed per year until 2018, when cases per year dropped from 46 to 6 or below for the remaining 3 years (2018, 2019, 2020). Of these 314 patients, 16 were male and 298 were female. (5.1% and 94.9%, respectively). The average age of diagnosis was 69.6 years with a standard deviation of 11.8 and a range of 30 to &gt; 90 years. The majority (99.7%) were found in the breast, with the remaining found in the endometrium. The majority of individuals (82.2%) had Charlson-Deyo comorbidity scores of 0. The majority of patients were non-Hispanic White, accounting for 88.9% of the total. A higher number of patients belonged to the highest income bracket, with 35.0% in the top quartile compared to those in other quartiles. The majority of patients had Medicare insurance, making up 63.1% of the total. More patients resided in counties with over 1 million people (56.7%) compared to those living in counties with a population below 1 million (43.3%). Most patients were treated at non-academic cancer centers (65.6%). On average, patients lived 19.8 miles (SD = 74.7, range = 1.8 – 370) from the treatment facility. Conclusions: Based on our literature review, this is the first NCDB analysis on EPC and thus addresses a significant knowledge gap on the topic. With an average age of diagnosis at 69.6 years, it is not surprising that the majority of patients were insured through Medicare. Male cases, while rare, support previous literature. Most commonly, EPC patients were most diagnosed in metropolitan areas. The majority of cases were diagnosed in the breast and most patients were treated at non-academic medical centers. While the vast majority of cases occurred in non-Hispanic white patients, it is unclear how much is due to race and how much is related to disparities in healthcare access and underdiagnosis in non-white races. Thus, further research is needed to understand which demographic factors prove to be the strongest predictors of EPC.
Phase IIa study of αDC1 vaccines targeting HER2/HER3 combined with pembrolizumab in patients with asymptomatic brain metastasis from triple negative breast cancer or HER2<sup>+</sup> breast cancer.
Authors: Shipra Gandhi, Peter A. J. Forsyth, Mateusz Opyrchal, Kamran A. Ahmed, Kristopher Attwood, Ellis Glenn Levine, Tracey L. O'Connor, Amy P. Early, Robert Alan Fenstermaker, Dheerendra Prasad, Kazuaki Takabe, Brian J. Czerniecki, Pawel Kalinski
Journal: Journal of Clinical Oncology (2023)

TPS1112 Background: Brain metastases develop in up to 50% patients (pts) with metastatic triple negative breast cancer (TNBC) and HER2 + BC, constituting an increasing source of morbidity and mortality. HER3, overexpressed in triple negative and HER2 + brain metastatic breast cancer (BMBC), is a resistance factor to HER2-targeted therapies and a driver of CNS metastasis. Disease progression is associated with loss of anti-HER2 and anti-HER3 immunity. Previously, we have demonstrated that glioma-specific peptide-loaded αDC1 which produce CXCL9, CXCL10, CXCL11, CCL5, the chemokines which attract CXCR3- and CCR5- expressing cytotoxic T-lymphocytes (CTLs) and T-helper 1 (Th1) cells, induce clinical responses and long-term disease stabilization in pts with aggressive recurrent primary brain tumors (Okada et al. JCO 2011. PMID: 21149657). We hypothesized that anti-HER2/3-loaded αDC1 in combination with PD1 blockade will result in strong Th1/CTL response against HER2/3 epitopes (Basu A et al. Cancer Immunol Res. 2022 PMID: 34785506), being effective against brain lesions and systemic disease. Methods: This is a phase II single-arm, non-randomized multicenter study (NCT04348747). Eligibility includes pts with triple negative and HER2 + BMBC ≥18 years, ECOG PS ≤1, normal marrow and organ function with asymptomatic untreated brain metastases ≥ 5 mm who will receive αDC1 q3 weeks x 3 along with pembrolizumab every 3 weeks. Thereafter, αDC1 booster doses (if available) would be administered every 3 months until disease progression, intolerable side effects or withdrawal from study, up to 24 months. Baseline and 9-week post-αDC1 peripheral biopsies (non-CNS) are required for six pts. 1 of the planned 21 pts have been enrolled and is undergoing treatment. Primary endpoint is CNS response rate (RR) by RANO-BM criteria. If no CNS response is observed after 12 pts, study will be terminated. If ≥ 1 response observed, then 9 more pts will be enrolled, for a total of 21 pts. If ≥ 3 CR are observed, the proposed therapy will be considered as promising for further evaluation. Secondary endpoints include non-CNS RR per RECIST v1.1, median CNS, non-CNS and overall progression-free survival, overall survival and safety. Exploratory endpoints include changes in intratumoral biomarkers (CTLs, PDL1, chemokines) in pre- and post-treatment peripheral tumor biopsies and immune changes in the blood. Clinical trial information: NCT04348747 .
RNA expression levels from peripheral immune cells, a minimally invasive liquid biopsy source to predict response to therapy, survival and immune-related adverse events in patients with triple negative breast cancer enrolled in the GeparNuevo trial.
Authors: Hanna Huebner, Matthias Rübner, Andreas Schneeweiss, Carsten Denkert, Hans Peter Sinn, Michael Braun, Thomas Karn, Bruno Valentin Sinn, Dirk Michael Zahm, Jörg Thomalla, Jens Bodo Huober, Claus Hanusch, Michael Untch, Christine Solbach, Theresa Link, Natalie Filmann, Julia Rey, Sibylle Loibl, Peter A. Fasching
Journal: Journal of Clinical Oncology (2023)

1011 Background: The impact of immune checkpoint therapy on the tumor microenvironment including tumor-infiltrating immune cells is well described. However, little is known about the circulating immune repertoire and its association with treatment outcome. Hence, we set out to investigate the RNA phenotype of peripheral immune cells before and during treatment of patients enrolled in the GeparNuevo trial (Loibl S et al. Annals Oncol 2022). Methods: The GeparNuevo trial investigated the outcome after neoadjuvant nabP-EC-chemotherapy in combination with the anti-PD-L1 immune checkpoint inhibitor durvalumab versus placebo in patients with non-metastatic triple negative breast cancer. Blood was collected before therapy (baseline), after window, before epirubicin/cyclophosphamide and at end of treatment. RNA from circulating leucocytes of 117 patients was extracted and analyzed using a custom NanoString nCounter CodeSet. Expression of 290 immune-related genes was quantified. The association of RNA expression and signatures with outcome parameters like pathologic complete response (pCR), distant disease-free survival (DDFS), invasive disease-free survival (iDFS), overall survival (OS), and immune-related adverse events (irAEs) were investigated. Results: Immune cell type scores representing macrophages and neutrophils significantly increased during treatment, while B cell, T and Th1 cell scores decreased (p &lt; 0.0001, respectively) regardless of treatment arm. Multivariate logistic respectively multivariate Cox regression analysis revealed a significant association of each baseline DPP4 and MYC gene expression with pCR, DDFS, iDFS, and OS in patients. CDK2, F5 and HLA-DR mRNA expressions were associated with the presence of irAEs. The signature score for TNFR2 non-canonical NF-kB pathway, which is known for its protective capacity, was inversely associated with irAEs in the durvalumab arm (OR = 0.454, 95% CI 0.231-0.892, p = 0.0220). Multiple immune-related signatures at baseline were associated with tumor mutational burden. Conclusions: Our study indicates the importance of the peripheral immune phenotype for treatment response and survival. This association between RNA expression levels of circulating immune cells and outcome seems to be not only relevant for patients receiving immune checkpoint therapy, but also for those under standard chemotherapy alone. Clinical trial information: NCT02685059 .
Individualized treatment estimates to inform on personalized cancer care decisions for treatment selection and treatment management.
Authors: David Walsh, Sumana Srivatsa, Renee George, Ben Ellis, Mayada Aljehani, Mitchell E. Gross, Reva K. Basho, Naim Matasci, Christine Swisher
Journal: Journal of Clinical Oncology (2023)

e13571 Background: Clinical trials report average effects of treatments at a population level. However, clinicians must balance treatment benefits against risks to personalize therapy. Here, we present a statistical framework which incorporates real-world data to estimate efficacy and symptom burden for an individual patient. We then assess the potential impact of continuing immunotherapy beyond progression in patients with metastatic solid malignancies on immune-related adverse events, progression, and survival. Methods: We corrected for sampling biases with inverse propensity score weighting (IPTW), and used the IPTW-transformed data to train predictive models of patient outcomes under each option. The models utilize a peer-based similarity based on 222 routinely-collected patient characteristics, such as cancer and treatment specific factors, laboratory tests, demographics, vitals, stage, comorbidities and symptoms, which are extracted from the electronic health record or natural language processing of clinician narratives, and Social Determinants of Health from Census data. We developed our methods on “Dataset A”: 5,919 breast and genitourinary (GU) cancer patients at a tertiary cancer center. We computed individualized treatment effect (ITE) estimates on “Dataset B”: 5,486 breast, GU, and thoracic cancer patients who received immunotherapy. Results: Our approach eliminated biases in Dataset A: the IPTW-transformation reduced the between-group standardized mean difference across identified confounders from an average of 0.225 to an average of 0.022. The similarity model exhibited strong discrimination (ROC-AUC &gt; 0.75), and identified associations between patient characteristics and outcomes that matched clinicians’ expectations. Validations are ongoing to assess the ITE estimates on a held-out subset of Dataset B. These include subgroup analyses for metastatic triple-negative breast cancer and non-small cell lung cancer. Conclusions: We introduce a method to estimate the efficacy and toxicity of interventions, actions, or treatment decisions, which replicates the statistical robustness of a clinical trial while obtaining individualized insights. This framework provides causal estimates of symptom burden and risks of progression and survival to inform clinical decisions, including continuation of immunotherapy beyond progression. After IPTW, confounders in Dataset A were balanced between the treatment groups, with weighted standardized mean differences &lt;0.1. [Table: see text]